Abstract Cellular immune responses play a crucial role in controlling viral replication in HIV-infected individuals. An optimal anti-HIV T cell response is critical for clearing HIV infected cells and central for HIV cure strategies. However, chronic immune activation drives the pathogenesis of HIV-1 infection, leading to loss of CD4+ T cells and exhaustion of antiviral cellular immunity, which is characterized by poor anti-viral responses against HIV. Autophagy, a homeostatic mechanism that involved in the disposal of damaged cellular organelles and elimination intracellular pathogens, is intricately involved in T cell function but it is impaired during HIV infection. In this this study, we will investigate the role of autophagy for HIV immuno-pathogenesis and examine if improving autophagy during chronic HIV infection can restore exhausted anti-viral responses. We will use the humanized mouse model of HIV infection, which mimics HIV immune exhaustion observed in HIV infected patients. We will study the following two aims: 1) Investigate how chronic HIV infection affects T cell autophagy and examine if autophagy inducer treatment can restore/improve exhausted anti-HIV T cells response in vivo. We will examine if inducing autophagy will improve HIV specific T cell autophagy, remodel T cell metabolism, reduce expression of inhibitory receptors and directly improve their functions in vivo.; 2) Investigate the role of autophagy in chronic inflammation during chronic HIV infection and examine if autophagy inducer treatment reduces persistent immune activation, alleviates immune suppression, and indirectly improves anti-viral T cell functions in vivo.